Hepatic tolerance was initially demonstrated by spontaneous acceptance of liver allografts in pigs, and subsequently in rats and mice. In humans, rejection of liver transplants is a common occurrence, which is, however, easy to control. There are well-documented cases in which liver grafts survive for years after discontinuation of immunosuppressive therapy. Vulnerability of livers to chronic infection (hepatitis and parasitic infection) and cancerous metastasis has also been attributed to the tolerogenic properties of the liver. The involved mechanisms are unclear. Accumulating data have demonstrated however, that hepatic tolerance is associated with activated T cell apoptosis probably via differentiation of T regulatory cells. These observations support our hypothesis that the liver has the potential to promote apoptotic death of activated antigen-specific T cells, and generate T regulatory activity. The overall goal of this proposal is to yield insights into the underlying mechanisms using T cell receptor (TCR) transgenic mice. There are four Specific Aims. In Specific Aim 1, we will characterize the responses of both CD4+ and CD8+ TCR transgenic T cells to the antigens that are exclusively expressed in the liver. The use of this system will also allow us to precisely test whether tolerance towards the antigen expressed in the liver is local or systemic, and whether it involves attenuation of affector or effector arms of the immune response (Specific Aim 1). The nature of antigen presenting cells (APC) in the liver is another area that has mostly been investigated in vitro, but little has virtually been explored in vivo or ex vivo, despite the suggested central role of these cells in regulating tolerance induction. Thus, we will characterize the behavior, antigen-presenting capacity of liver APC and interaction with T cells (Specific Aim 2). In Specific Aim 3 and 4, we will ascertain the mechanisms of two key events occurring in hepatic tolerance: activated T cell apoptosis and T regulatory cell differentiation, both of which are believed to be crucial in induction of peripheral immune tolerance. We will determine how the liver induces activated T cell death (Specific Aim 3), and the role of T regulatory activity in hepatic tolerance (Specific Aim 4). We believe that these focused relevant studies will provide better understanding of liver immunity and facilitate novel therapeutic strategies to combat chronic liver diseases.